Gene therapy for rare diseases

What are rare diseases?

Rare diseases, also known as very infrequent diseases, are potentially fatal or chronic and degenerative. The number of people affected is five per 10,000. Most of these diseases are of genetic origin and over 50% of them affect children. Currently it is calculated that in the European Union there are between 5000 and 8000 different rare diseases suffered by between 6 and 8% of the population, that is, between 27 and 36 million people. In Spain over 3 million people are affected.

What do we research?

Our laboratory focuses on understanding the pathophysiology of some of these rare diseases and on developing new therapeutic strategies based on gene transference, which may offer solutions for these pathologies.

We are using AAV vectors to achieve the sustained correction of the gene deficiency in these genetic diseases. Simultaneously, we are working on the improvement of gene transference vehicles, as a result of a better knowledge of the vector at a molecular level, and on the design of protein expression systems to create more effective therapies.

Our priority research is into two of these diseases: Dravet Syndrome and hyperoxaluria. Besides, this research favors advances in the development of therapy for another 300 rare diseases.

Additionally, we are collaborating with other research programs in CIMA focusing on other rare diseases:

Development of a gene therapy treatment (vector design and analysis for effectivity and toxicity) for acute intermittent porphyria (AIP) used in a phase I clinical trial at the Clínica Universidad de Navarra. Some of the patients treated have shown a certain improvement which drives us to continue with the development of these advanced techniques.

Development of similar strategies for hyperoxaluria.

Diseases we research as a priority in our laboratory

Dravet Syndrome

Research group leader: Dr. Rubén Hernández.

What it is: Dravet Syndrome is a rare genetic disease with one case occurring per 20,000 people. It is one of the most severe congenital epilepsies. It causes very frequent convulsions, occasionally long-lasting, which do not respond well to conventional pharmacological treatment. These symptoms usually begin at around four months of age. Later, it causes neurological disorders and intellectual disability. In over 80% of cases the cause is a mutation in the SCN1A gene, which results in a reduction of a sodium channel in the neurons responsible for controlling the propagation of nerve stimuli in the brain. In most cases these are new mutations in the individual, with no previous family history...

Objective: This disease offers a major challenge due to the size and relative instability of the SCN1A gene, and the complexity of its functions in the brain. For this reason, the Gene Therapy and Neurosciences programs at CIMA, in close collaboration with the Pediatric Department of the Clínica Universidad de Navarra, have initiated a project to transfer the corrected gene to the neurons by using high-capacity adenoviral vectors and to control its expression as physiologically as possible. Currently we are in the development phase of these vectors and assessing the most suitable regulatory sequences. For testing in animal models we are implementing an advanced model of the disease in mice, developed by the Fundación Síndrome de Dravet.

Hyperoxaluria

Research group leader: Dr. Gloria González Aseguinolaza.

What it is: Type I primary hyperoxaluria (PH1) is a rare metabolic disease caused by mutations in the AGXT, which encodes AGT. The absence of AGT leads to the blockage of the glyoxylate detoxification route and, consequently, to the accumulation of oxalate crystals in the kidney. The patients present with serious renal damage and the only remedial treatment is a liver transplant, in addition to a kidney transplant in most cases.

Objective: In collaboration with the Dutch company uniQure and European clinical groups we are working on the optimization of a therapeutic vector for this disease with funding from the American Oxalosis and Hyperoxaluria Foundation (OHF). Additionally, in collaboration with the Cell Therapy groups at CIMA, the Universidad de La Laguna and CIEMAT, we are working on the development of gene correction strategies to treat the disease.

"Our laboratory is working on developing new treatments for liver diseases, based on gene transfer using one of the safest and most effective viral vectors currently in existence: the adeno-associated virus. In the next few years, we hope to obtain a clear clinical benefit in patients with rare diseases such as hyperoxaluria", Dra. Gloria González, Program Director.